Sodium fluoride induces apoptosis in mouse embryonic stem cells through ROS-dependent and caspase- and JNK-mediated pathways

Abstract

Sodium fluoride (NaF) is used as a source of fluoride ions in diverse applications. Fluoride salt is an effective prophylactic for dental caries and is an essential element required for bone health. However, fluoride is known to cause cytotoxicity in a concentration-dependent manner. Further, no information is available on the effects of NaF on mouse embryonic stem cells (mESCs). We investigated the mode of cell death induced by NaF and the mechanisms involved. NaF treatment greater than 1 mM reduced viability and DNA synthesis in mESCs and induced cell cycle arrest in the G2/M phase. The addition of NaF induced cell death mainly by apoptosis rather than necrosis. Catalase (CAT) treatment significantly inhibited the NaF-mediated cell death and also suppressed the NaF-mediated increase in phospho-c-Jun N-terminal kinase (p-JNK) levels. Pre-treatment with SP600125 or z-VAD-fmk significantly attenuated the NaF-mediated reduction in cell viability. In contrast, intracellular free calcium chelator, but not of sodium or calcium ion channel blockers, facilitated NaF-induced toxicity in the cells. A JNK specific inhibitor (SP600125) prevented the NaF-induced increase in growth arrest and the DNA damage-inducible protein 45α. Further, NaF-mediated loss of mitochondrial membrane potential was apparently inhibited by pifithrin-α or CAT inhibitor. These findings suggest that NaF affects viability of mESCs in a concentration-dependent manner, where more than 1 mM NaF causes apoptosis through hydroxyl radical-dependent and caspase- and JNK-mediated pathways.

Single oral acute fluoride exposure causes changes in cardiac expression of oxidant and antioxidant enzymes, apoptotic and necrotic markers in male rats

“…These results suggest that acute F -intoxication induced mitochondrial apoptosis in the cardiomyocytes through oxidative disruption of the mitochondrial membrane potential and initiated the translocation of Bax from cytosol to mitochondria, led to the release of cytochrome c, subsequently activates the caspase cascade [32]. In addition to this, TUNEL labelling is the hallmark of apoptosis.…”

“…Myocardial ROS, LPO, PCC and M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 16 NO are the hallmarks of oxidative insults triggered by various xenobiotics [30][31]. F -is known to induce oxidative stress that has been well demonstrated in several in vitro models [32][33] and in vivo chronic toxicity in experimental animals [34][35] and humans [16]. For the first time we report that acute F -toxicity impairs cardiac function through oxidative myocardial injury.…”

“…It has been well documented that induction of apoptosis in Ftoxicity in both chronic in vivo [30,35] and in vitro models [32][33]. Nevertheless, whether acute fluoride exposure may induce myocardial apoptosis mediated cardiotoxicity remained unknown.…”

High Density Lipoprotein Protects Mesenchymal Stem Cells from Oxidative Stress-Induced Apoptosis via Activation of the PI3K/Akt Pathway and Suppression of Reactive Oxygen Species

“…Excessive production of ROS has been shown to damage stem cells through caspase-mediated pathways [20]. Therefore, these findings suggested that HDL activation of the PI3K/Akt pathway might inhibit ROS generation, and thereby reduce apoptosis of implanted MSCs.…”

Effect of oxidative stress on fluoride-induced apoptosis in primary cultured Sertoli cells of rats

“…Wang et al (2011) suggested that NaF-induced apoptosis may contribute to increased oxidative stress damage in primary mouse osteoblasts. Nguyen Ngoc et al (2012) found that sodium fluoride induces apoptosis in mouse embryonic stem cells, which was related to ROSmediated signaling pathway. Jacinto-Alemán et al (2010) reported that cell apoptosis of ameloblasts and odontoblasts induced by fluoride was related to oxidative stress due to the reduction of the enzymatic antioxidant.…”